Certain 5-nitro-2-furyl-1, 2, 4-triazoles



United States Patent 3,277 110 CERTAIN S-NITRO-Z-FllRYL-LZA-TRIAZOLESHomer Albert Burch, Norwich, N.Y., assignor to The Norwich PharmacalCompany, a corporation of New York' No Drawing. Filed Mar. 10, 1965,Ser. No. 438,743 7 Claims. (Cl. 260-308) This application is acontinuation-in-part of my copending application Serial No. 336,643,filed January 9, 1964.

This invention relates to new chemical compounds. More particularly, itis concerned with a new series of nitrofuran compounds,-nitro-2-furyl-1,2,4-triazoles of the formula:

wherein R is a member of the group consisting of hydrogen and loweralkyl, preferably 1-4 carbon atoms; and R is a member of the groupconsisting of hydrogen, methyl, acetyl and methylcarbamoyl.

These new compounds possess a high order of antibacterial activity beinginirnical in very small amounts to gram-positive and gram-negativebacteria such as Staphylococcus aureus, Streptococcus pyogenes,Escherichia coli, Proteus vulgaris and Erysipelothrix insidiosa. Theyare thus adapted to be combined with conventional, commonly usedcarriers to form disinfectant compositions. In such use they arecommonly compounded in the form of dusts, sprays, suspensions,solutions, tablets, ointments and the like using excipients andadjuvants well known in the art for such purpose.

The compounds of Formula I are not limited in their antibacterialefficacy to solely in vitro efiect; for, upon oral administration toanimals infected with pathogenic organisms such as Staphylococcusaureus, Salmonella typhosa or Escherichia coli, they provide protectionagainst death. Thus, when administered perorally to mice lethallyinfectedby the aforementioned organisms in doses of from 40-150 mg./kg.,they are capable of preventing mortality due to such infective forces.Such administration also presents antibacterial serum levels of thesecompounds making them valuable systemic chemotherapeutic.

The preparation of the compounds of Formula I wherein R is aforesaid isreadily carried out. The method which is currently preferred consists incontacting an N- alkanoylamido-S-nitro-2-furamidine with an agentcapable of causing ring closure. Suitable agents for this purpose arephosphorus oxychloride or glacial acetic acid. It is advantageous tosupply heat to the mixture to hasten the reaction. When the reaction iscomplete, the mixture is quenched and the solid product filtered. Forpurification purposes the solid may be recrystallized from suitablesolvents such as aqueous solutions of ethanol or acetic acid. Theintroduction of the appropriate R substitueut is readily accomplished bymeans of an acylating agent such as acetic anhydride or methylisocyanate or by means of an alkylating agent such as methyl iodide inthe presence of a base.-

In order that this invention may be fully available to and understood bythose skilled in the art, the followin illustrative examples arepresented:

EXAMPLE I 5-methyl-3-(5-nitro-2-furyl)-1H-1,2,4-triazole (NF-1030) A2-1., 3-neck flask, fitted with a stirrer, condenser, and a stopper ischarged with 50 gms. (0.68 mole) of acetyl hydrazide, 150 gms. (0.68mole) of ethyl 5-nitro- 2-furamidate hydrochloride, 38 gms. (0.7 mole)of sodium methylate, and 850 ml. of methyl alcohol. The mixture isheated on a steam bath for 30 minutes. After evaporating the methylalcohol in vacuo on a Warm water bath, the residue is poured into Waterto give a brown solid in a yield of gms. (83.5%). This crude product (50gms.) is slurried in acetone to give the 43 gms. ofN-acetamido-S-nitIo-Z-furamidine melt ing at 217-218. It may berecrystallized from ethanol to raise the melting point to 224-225".

Anal.Calcd. for C7H5N4O4: C, 39.64; H, 3.80; N, 26.41. Found: C, 39.76,39.79; H, 4.06, 4.11; N, 26.32, 26.35.

METHOD A A solution of 51.0 g. (0.24 mole) ofN-acetamido-S-nitrO-Z-furamidine in 200 ml. of phosphorus oxychloride isrefluxed for- 1 hour. The cooled mixture is poured into ice water andstirred for =1 hour. The crude product is collected by filtration,Washed with cold water and air dried to give a yield of 23.3 g. (50%).Recrystallization from dilute aqueous ethanol gives the title product aspale yellow needles melting at 254.5-256 dec.

Anal.Calcd. for C H N O C, 43.30; H, 3.12; N, 28.86. Found: C, 43.39,43.36; H, 3.46, 3.28; N, 28.69, 28.78.

METHOD B A solution of 40.0 g. (0.19 mole) of N-acetamido-S-nitro-2-furamidine in 200 ml. of glacial acetic acid is refluxed forthree hours. Upon cooling the mixture, the title product separates ast-an crystals which are filtered, washed with Water and dried at 60 togive 28.0 g. (76.5%); M.P. 250255 dec.

EXAMPLE II 5-ethyl-3- (S-nitro-Z-furyl) -1H-1,2,4-triazole (NF-1045) Toa solution of 10.5 g. (0.195 mole) of sodium methylate in 380 ml. ofmethanol is added 43 g. (0.195 mole) of ethyl 5-nitro-2-furamidatehydrochloride and 17.2 g. (0.195 mole) of propionyl hydrazide. Theresulting mixture is boiled for 45 minutes. The solvent is removed invacuo on a steam bath and the residue is stirred in 500 ml. of icewater. The crude product is collected and recrystallized from ethanol.The product, N-propionamido-S-nitIo-Z-furamidine, separates as redneedles melting at 204205 in a yield of 21.6 g. (49% Additionalrecrystallizations raise the melting point to 207-2075".

Anal.Calcd. for C H N O C, 42.48; H, 4.46; N, 24.77. Found: C, 42.56,42.44; H, 4.54, 4.49; N, 24.48, 24.41.

A solution of 80.0 g. (0.35 mole) of N-propionamido-5-nitro-2-furamidine in 240 ml. of glacial acetic acid is refluxed forca. 4 hours. The hot reaction mixture is treated with charcoal andfiltered by suction. The filtrate is diluted with an equal volume ofwater and chilled. The crude product is collected by filtration andwashed with cold water. Recrystallization from dilute aqueous aceticacid gives the title product as light tan needles melting at 181.5183.5in a yield of 37.7 g. (51.5%).

Alzal.Calcd. for C H N O C, 46.15; H, 3.87; N, 26.92. Found: C, 46.08,46.21; H, 3.94; 3.75; N, 26.84, 26.66.

EXAMPLE III 3- (5 -nitro-2-furyl -1 H ,2,4-triazole (NF-1065) To asolution of 30.0 g. (0.55 mole) of sodium methylate in 1 l. of methanolis added 121 g. (0.55 mole) of ethyl 5-nitro-2-furamidate hydrochlorideand 33.0 g. (0.55 mole) of formhydrazide. The solution is boiled for 1hour after which the solvent is removed in vacuo on a steam bath. Theresidue is shaken with 400 ml. of ice water and filtered.Recrystallization of the solids from ethanol gives the product,N-formamido-5-nitro-2-furarnidine, as yellow needles in a yield of 27.3g. Dilution of the filtrate with 250 ml. of water and further chillinggives an additional 6.2 g. The total yield is 33.5 g. (30.6%). Theproduct melts at ca. 180, solidifies and decomposes at 25 9260Anal.Calcd. for C H N O C, 36.37; H, 3.05; N, 28.28. Found: C, 36.59,36.65; H, 3.34, 3.22; N, 28.27, 28.39.

A solution of 34 g. (0.17 mole) of N-formamido-S-nitro-2-furamidine in110 ml. of glacial acetic acid is refluxed for 4 hours. The mixture ischilled and the crude product is collected 'by filtration.Recrystallization from dilute aqueous acetic acid gives the titleproduct as pale tan micro crystals decomposing at 252-254 in a yield of8.4 g. (27.4%). Further recrystallization raises the decomposition pointto 259260.

Anal.-Calcd. for C H N O C, 40.01; H, 2.24; N,

31.31. Found: C, 40.00; H, 2.26; N, 31.53.

EXAMPLE 1V 1-methylcarbam0yl-3-(S-nitro-Z-furyl)-1H-1,2,4-triaz0le(NF-1223) A solution of 50 g. (0.278 mole) of the compound of ExampleIII in 300 ml. of dimethylformamide containing 50 ml. of methylisocyanate is heated on a steam bath with stirring for 45 minutes. Thehot solution is treated with charcoal, filtered, cooled, diluted with300 ml. of water and chilled thoroughly. The product is filtered andwashed thoroughly with water. Recrystallization is effected rapidly bytreating portions of the product with boiling ethanol, filtering themixture rapidly by suction and cooling the filtrate as quickly aspossible. The title product separates as long yellow needles melting at188190 (corn) with resolidification and decomposition at 257- 259(corr.). The yield is 31.5 g. (47.7%).

Anal.Calcd. for C H N O C, 40.51; H, 2.97; N, 29.53. Found: C, 40.75; H,3.18; N, 29.45.

EXAMPLE V 1-acetyl-3-(5-nitro-2-furyl) -1H-1,2,4-triaz0le (NF-1226) Asolution of 45 g. (0.25 mole) of the compound of Example III in 300 ml.of acetic anhydride is heated on a steam bath for 2 hours. The solventis removed in vacuo after which the residue is recrystallized fromethanol. The product separates as pale yellow needles melting at 167168(corn) in a yield of 38.6 g. (69.5%

4 Anal.Calcd. for C H N O C, 43.25; H, 2.72; N, 25.22. Found: C, 43.40;H, 2.72; N, 25.28.

EXAMPLE VI 1 ,5 -dimezhy [-3- 5 -ni tr0-2-furyl -1 ,2,4 -Iriazole (NF 11 03) To a stirred suspension of 40 g. (0.21 mole) of the compound ofExample I in 1 l. of methanol is added 11.3 g. (0.21 mole) of sodiummethylate. After refluxing the mixture for 20 minutes, 40 ml. of methyliodide is added dropwise during 10 minutes. The mixture is refluxed foran additional 1.5 hours. The solvent is removed in vacuo on a steambath; the residue is slurried with cold Water and filtered.Recrystallization from methanol gives the title product as yellowneedles melting at 178480 in a yield of 15 g. (34.4%). Recrystallizationraises the melting point to 1845- (corn).

Anal.-Ca1cd. for C H N O C, 46.15; H, 3.87; N, 26.92. Found: C, 46.25;H, 4.06; N, 26.76.

What is claimed is:

1. A compound of the formula:

mil 1.

wherein R is a member of the group consisting of hydrogen and loweralkyl; and R is a member of the group consisting of hydrogen, methyl,acetyl and methylcarbarnoyl.

2. 5-methy1-3-(5-nitro-2-furyl)-1H-1,2,4-triazole.

3. 5-ethyl-3-(5-nitro-2-furyl)-1H-1,2,4-triazole.

4. 3-(5-nitro-2-furyl)-1H-1,2,4-triazole.

5. l-acetyl-3-(5-nitro-2-furyl)1H-1,2,4-triazole.

6. 1-methylcarbamoyl-3-(5-nitro-2-furyl)-1H-1,2,4-triazole.

7. 1,5 -dimethyl-3- (5 -nitro-2-furyl) -1H- 1 ,2,4-triazole.

References Cited by the Examiner UNITED STATES PATENTS 2,723,274 11/1955Kaiser 260-308 2,898,343 8/1959 Klingsberg 260--3 08 2,953,491 9/1960Hardy et al 16733 2,959,518 11/ 1960 Speziale et al. 167-33 ALEX MAZEL,Primary Examiner.

ALTON D. ROLLINS, Assistant Examiner.

1. A COMPOUND OF THE FORMULA: